The present invention relates to chemical compounds having pharmacological activity. More particularly, this invention concerns certain .alpha.-.lambda.(2-nitro-1H-imidazol-1-yl)methyl]-aziridinylethanols and the corresponding aziridine ring opened analogs and their use as radiation sensitizers for radiation therapy of tumors.
One of the most serious probems encountered during X-ray radiotherapy of tumors is the relative resistance of hypoxic tumor cells to destruction. This resistance to radiotherapy is directly related to the lack of oxygen in these cells, and doses of X-ray have to be about three limes higher to kill a given proportion of hypoxic cells than of well-oxygenated cells. Oxygen is the main radiosensitizer during X-ray radiation therapy.
The presence of hypoxic cells in tumor tissue has been demonstrated repeatedly in animal tumors and their presence results in resistance to radiation, which makes cures with a single dose of X-rays difficult or impossible. (See G. E. Adams et al., Chemotherapy, Vol. 7, PP 187-206, Plenum Press, New York, 1976). The resistance of hypoxic cells to destruction by X-rays is also a serious limitation to attempts to increase the therapeutic ratio between tumor and normal tissue damage in radiation therapy. Tumors containing hypoxic cells which are able to reoxygenate are more susceptible to fractionated radiotherapy, and this probably accounts for the reason cures are achieved at the present time.
To overcome the problem of the resistance of hypoxic cells to radiation therapy, patients have been irradiated in hyperbaric oxygen chambers. Although much experience has been gathered with this method, it is cumbersome and slow to use. The shut down of blood vessels is also a serious problem associated with this method.
Another solution to the problem has been the use of fast neutron or negative .pi. meson radiation, rather than X-rays. Although neutron radiation therapy is quite effective in treating some types of tumors, the method is very expensive and beyond the technical capability of most hospitals.
A third solution is the use of chemical substances which simulate oxygen in their ability to radiosensitize hypoxic tumor cells. Because these compounds distribute throughout the body, it is important that they concentrate more heavily in hypoxic tumor cells in order for them to be effective and prevent unwanted radiation damage to healthy tissue.
In 1963, Adams et al. (Biophysic. Res. Comm., 12: 473 (1963)) proposed that the ability of compounds to sensitize hypoxic bacterial cells is directly related to their electron affinity. This idea has been generally verified and has aided the search for more active compounds.
ln 1973, J. L. Foster and R. L. Wilson (Brit. J. Radiol., 46: 234 (1973)) discovered the radiosensitizing action of the antiprotozoal drug metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol). Metronidazoe is active both in vitro and in vivo in animals as a radiosensitizer.
Another antiprotozoal agent, misonidazole (.alpha.-(methoxymethyl)-2-nitro-1H-imidazoe-1--ethanol), has also recently proven to be of value as a radiosensitizer for hypoxic tumor cells (J. D. Asquith, et al., Rad. Res., 60: 108 (1974)).
Both metronidazole and misonidazole are effective in vivo. However, both compounds exhibit serious adverse CNS side effects when administered orally to mice. They exhibit peripheral neuropathy effects and convulsions in mice and their CNS toxicity is a limiting factor for their use in humans. Nevertheless, the activity of these compounds as radiosensitizers has led to interest in the class of substituted 2-nitro-1H-imidazole-1-ethanol compounds and spurred the search for ompounds of this class having enhanced activity and diminished undesirable CNS side effects.
U.S. Pat. No. 4,282,232 to Agrawal discloses certain N-oxides of nitrogen-heterocyclically substituted 2-nitro-1-ethyl-1H-imidazoles useful as radiosensitizing agents.
U.S. Pat. 4,581,368 (and its division, U.S. Pat. No. 4,596,817) disclose certain 2-nitro-1H-imidazolyl-1-[.OMEGA.-(1-aziridinyl)alkanols] useful as radiosensitizing agents.